Autism is an increasingly common disorder of complex etiology, affected by both genetic and environmental influences. Autism has several phenotypic features in common with the neurodevelopmental disorders Rett syndrome and Angelman syndrome. Rett syndrome (RTT) is an X-linked dominant disorder caused by mutations in MECP2, which encodes methyl-CpG-binding protein 2 (MeCP2). Methylation of CpG dinucleotides and methyl-specific binding proteins are part of an epigenetic pathway essential for parental imprinting and chromatin dynamics during normal brain development. Angelman syndrome (AS) is an imprinted disorder caused by maternal deficiency of chromosome 15q11-13. In addition, MECP2 mutations have been found in a few patients diagnosed with AS and autism and 15q11-13 duplications are the most common cytogenetic abnormality found in autism. Together these findings support the broad premise that these three distinct genetic syndromes share overlap in their pathogenic mechanisms. This research proposal will focus on the hypothesis that MECP2 regulates gene expression in the 15q11-13 region, and that aberrations in this regulatory pathway may contribute to phenotypic features of autism-spectrum disorders. The first aim of the proposal is to determine the effect of MeCP2 deficiency on gene expression in the imprinted 15q11-13 locus by several quantitative approaches. The second aim of the proposal is to determine the mechanism by which MeCP2 regulates gene expression within 15q11-13. The third aim is to investigate expression defects in MeCP2 and target genes in the 15q11-13 region in multiple autism brain samples. These studies aim to uncover important mechanistic similarities between the overlapping neurodevelopmental disorders RTT, AS, and autism. The successful completion of these studies should yield findings to help develop better diagnostic and treatment modalities for autism-spectrum disorders.